Therapeutic delivery system

ABSTRACT

Therapeutic delivery systems are provided which, in a first embodiment, contain a plurality of multiphase capsules in which first and second therapeutic agents are contained in separate phases within said multiphase capsules, and are disposed to deliver said first and therapeutic agents by at least two different delivery mechanisms.

RELATED APPLICATION DATA

This application is a continuation-in-part of application Ser. No.10/676,520, filed Sep. 20, 2003 (D0968-00044), which is a continuationof application Ser. No. 09/859,319, filed May 17, 2001 (D0968-00032),which is a continuation of application Ser. No. 09/099, 825, filed Jun.18, 1998 (D0968-00017), now U.S. Pat. No. 6,244,265, which is acontinuation-in-part of application Ser. No. 08/942,797, filed Oct. 2,1997, (D0968-00011) which is a continuation of application Ser. No.08/791,760, filed Jan. 29, 1997 (D0968-00009), now U.S. Pat. No.5,706,800.

FIELD OF THE INVENTION

This invention relates to therapeutic delivery systems and method oftreating patients, and more particularly to drug and therapeuticdelivery systems containing multiple delivery mechanisms.

BACKGROUND OF THE INVENTION

The nose has the important function of first contact with inspired air.This air is laden with pollutants, suspended material, microbes, andnoxious substances. Air can be cold and dry and often needs warning andhumidification before entering the lower respiratory tract. The nosealso serves as a sensitive detector of air-borne chemicals and helpssense the flavor of food and drink. The nose further serves an importantrole in the immune system because it is the first site of contact ofmany air-borne allergens with the body's defense system.

Many people have difficulty breathing through their nose. Some causesfor restricted breathing are congestion of the nasal lining fromallergies, deviation of the nasal septum, i.e., the partition betweenthe two nostrils, which narrows one or both nasal chambers, or by adroopy nasal tip.

During exercise, nasal breathing becomes more difficult and some peopleare forced to open their mouths to get enough air. When exercising, itis necessary to breath rapidly. Upon rapid breathing, a negativepressure is created in the nasal chamber forcing the lower sides of thenose to collapse which obstructs breathing. If nasal breathing becomesobstructed, it is necessary to breath through the mouth in order toobtain an adequate amount of air. When a person becomes a mouthbreather, the important functions of the nose are bypassed.

The nose accounts for approximately half of the total airway resistanceto airflow. Nasal obstruction can contribute to an increase in snoringand sleep apnea frequency and severity. Snoring sounds have beenassociated with increased upper airway occlusion. Upper airwaynarrowing, collapsability and resistance are recognized factorscontributing to snoring and obstructive sleep apnea. Certain loudsnorers have an increased internal resistive load that results inrepetitive arousals from sleep.

The nose is often affected by allergies, the flu or a cold. The commoncold, although not usually a serious illness, is a highly prevalent,discomforting and annoying affliction. The term is applied to minorrespiratory illnesses caused by a variety of different respiratoryviruses. While rhinoviruses are the major known cause of common colds,accounting for approximately 30 percent of colds in adults, viruses inseveral other groups are also important. While immune responses occur,and infection with some respiratory tract viruses therefore could beprevented by a vaccine, developments of a polytypic vaccine to cover allpossible agents is impractical. Thus, the problem of controlling acuteupper respiratory disease presents complex challenges, and thelong-desired discovery of a single cure for the common cold is anunrealistic expectation.

Early symptoms may be minimal with only mild malaise, sore throat andnasal complaints. With rhinovirus infection, symptoms of nasaldischarge, nasal congestion, and sneezing usually commence on the firstday of illness and progress to maximum severity by the second or thirdday. Along with nasal symptoms may come sore, dry or scratchy throat andhoarseness and cough. Other symptoms may include mild burning of theeyes, loss of smell and taste, a feeling of pressure or fullness in thesinuses or ears, headache, and vocal impairment. Fever can occur, but isuncommon. Influenza infection generally includes fever, often of suddenonset and persisting for several days, and with great severity;generalized aches and pains; fatigue and weakness; and chest discomfort.

The costs of treating colds with over-the-counter medications in theUnited States is estimated at an annual cost of over 1.5 billiondollars. The direct costs of treatment in outpatient clinics isestimated at almost four billion dollars. Indirect costs, based onamount of lost wages because of restricted activity are substantiallyhigher.

Nasal dilators have been suggested for aiding breathing through the noseduring snoring, athletic events, and for treating the symptoms of thecommon cold or flu. There have been traditionally two types of dilatorswhich have been effective in humans. One type uses small rings or cagesconnected to a resilient structure. The rings are inserted into eachnasal passage while the resilient structure spreads to provideunobstructed breathing. These dilators have been criticized because theyare often uncomfortable to wear. Since the cages or rings are insertedinto contact with sensitive nasal tissue, they have been known to causeirritation and itching. Such devices are disclosed in U.S. Pat. No.3,710,799 to Caballero and the NOZOVENT dilator disclosed in PetrusonD310,565.

More recently, advancements have been made in nasal dilators whichattach to the outer wall tissue of the nose and aid in preventing theinner nasal tissue from drawing in during breathing. Such dilatorsinclude a flexible strip of material adhesively attached to a substrate.The dilator is fastened to the nose and the resilient material acts tokeep the left and right nasal passages from drawing in or collapsingduring inhalation. This usually occurs due to a malformation, such as adeviated septum or due to swelling during allergic reactions and thelike. Examples of nasal dilators which are adhesively attached to theouter skin of a human nose are disclosed in Doubek et al., U.S. Pat. No.5,533,503 and Muchin, U.S. Pat. No. 5,546,929.

In related application U.S. Pat. No. 5,706,800, which is herebyincorporated by reference, there is disclosed a medicated nasal dilatorincluding essential fragrance oils, such as camphor and menthol. Suchfragrance oils are commonly used in the treatment of nasal congestion,bronchial asthma and cough suppression. They are widely available in theform of hard confection drops, nasal sprays and inhalers. The '800patent discloses a medicated nasal dilator having a resilient layer orportion which helps to provide mechanical dilation while theincorporated fragrance introduces an aromatic substance, preferably amedication, for treating the patient's symptoms.

Early attempts to produce medicated dilators have uncovered severalshortcomings that need to be addressed. Aromatic substances, such asmenthol and camphor, while therapeutically effective, are highlyvolatile. Oil-base carriers, such as petrolatum, commonly calledpetroleum jelly, while effective in containing volatile menthol andcamphor in airtight containers, quickly release these oily substancesinto the atmosphere when exposed to air. Accordingly, nasal dilatorsimpregnated with fragrance oils generally lose their odor quicklybecause the scent dissipates during the shelf life of the product.

Although hermetic foil packaging has been discussed, scented dilatorsremain relatively stable only until the packaging is opened. Withoutindividually wrapping each dilator, the remaining scented dilatorsdissipate their oils quickly. Separately packaging each dilator in itsown hermetic packaging, may improve shelf life, but it increases theexpense of the product and makes it generally more inconvenient to usedue to the tenacious materials, such as mylar, etc., used to makehermetic packaging. Additionally, such packaging fails to improve uponthe in-use duration of the fragrance when exposed to perspiration, bodyheat, dirt and dust, and the time demands of a full night's sleep.

Another drawback associated with scented dilators is the tendency of thenasal nerve endings to become desensitized to the fragrance, long beforethe fragrance has dissipated from the product. Due to the extendedperiods of time for which nasal dilators and strips are recommended,from an hour to 12 hours, prolonged exposure to the same volatile oil ormixture, such as menthol or camphor, generally engenders a phenomena ofadaptation called “olfactory saturation”, which results in a gradualloss of smell of the active fragrance to the wearer. This, of course, isa distraction to wearers, who may feel the need to replace the dilatorwith a fresh product, only to find that a new dilator fails tocompletely refresh the olfactory impression.

Fragrance oils are also known to break down the structure of knownpressure-sensitive adhesives used to attach nasal dilators to skin, suchas polyacrylate or polyvinylethyl ether blend adhesives. Such fragrancestend to migrate to the adhesive layer, even when they are incorporatedinto the fabric substrate. When fragrance oil mixes with the adhesive,it plasticizes the adhesive, making it less cohesive and more sticky.The internal strength of the adhesive is reduced considerably. This canhave the unfortunate, unintended effect of causing a nasal dilator,which is already exerting release pressure due to resilient memberscontained therein, to completely remove its adhesive attachment from thenose. To make matters worse, when it is desired to remove the dilator orstrip, portions of the plasticized adhesive remain on the skin surface,leaving it tacky and unsightly.

There also remains a concern relating to the proper dosage of fragranceoils used for nasal dilators and strips. If the fragrance oilconcentration is too high, it can irritate the eyes causing tears. Ifthe dosage is too low, there is insufficient fragrance to produce anolfactory effective amount, which, in the case of cosmetic fragrances,makes the product less appealing to the consumer, and in the case ofmedicated aromatics, renders these devices therapeutically ineffective.

Accordingly, there remains a need for improved delivery systems whichmay incorporate fragrances, transdermal medications and otheringredients. Such products remain an emerging technology, requiringinnovation to overcome the problems associated with short fragranceshelf life and in-use effectiveness, olfactory saturation, and dosageissues.

SUMMARY OF THE INVENTION

In a first embodiment of this invention, a therapeutic delivery systemis provided which includes a plurality of multiphase microcapsulescontaining first and second therapeutic agents and disposed to deliversaid first and second therapeutic agents by at least two differentdelivery mechanisms. Such therapeutic delivery systems can be used innasal dilators, adhesive strips, patches or in aromatic, oral, orintravenous administrations of medicine, therapeutic or diagnosticcompounds and actives (active ingredient), to patients suffering fromeverything from the common cold to cancer.

In a further embodiment of this invention, a medicated nasal strip isprovided which contains an elongated flexible layer sized to comfortablyfit across a bridge of a nose, a pressure-sensitive adhesive layerdisposed on the bottom surface of the flexible layer, and an aromaticsubstance disposed on a portion of the nasal strip in an olfactoryeffective amount. The nasal strip further contains extended releasemeans for extending the useful life of the aromatic substance.

In a further embodiment of this invention, a nasal strip is providedwhich contains an elongated flexible layer and a bio-compatible,pressure-sensitive adhesive disposed on a bottom surface of this layer.The nasal strip further includes an aromatic substance disposed on thenasal strip so as to avoid substantial contact and mixing with saidpressure-sensitive bio-compatible adhesive layer.

In a further embodiment of this invention, a nasal strip is providedwhich includes an elongated flexible member, bio-compatiblepressure-sensitive adhesive layer and an aromatic substance. This stripfurther includes a dual fragrance delivery system for minimizingolfactory saturation by the wearer.

In an effort to improve neat shelf life and dissipation of fragranceoils and medications during use, this invention may include extendedrelease means, including such individual fragrance delivery mechanismsas fixatives, gels, starches, carriers, porous hydrophilic inorganics,micro-capsules, cellulosic carriers, cyclodextrine coatings andbody-activated coatings, such as those which release fragrant oils uponachieving a certain temperature, reaching a certain pH, or, when theycome in contact with liquid perspiration. The fragrance deliverymechanisms of this invention help to contain the essence of the volatilearomatic compounds over a greater period of time to extend the shelflife, and increase the in-use olfactory effectiveness. Additional meansfor overcoming olfactory saturation are provided which include at leasttwo different fragrance or medication delivery systems and/or at leasttwo different fragrances or medications (or a fragrance and amedication). The different delivery systems can deliver an aromaticdrug, transdermal drug, and/or fragrance under different use conditions,or at different times during use to keep the product fresh to thewearer. For example, re-encapsulation can be used to release andpreserve fragrance oils or transdermal medications during the occurrenceand evaporation of perspiration during athletic events, or the rise andfall of body temperature, caused by viral infections or flu symptoms.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings illustrate preferred embodiments of theinvention as well as other information pertinent to the disclosure, inwhich:

FIG. 1: is a partial front perspective view of a man wearing thepreferred nasal dilator of this invention;

FIG. 2: is a top planar view a preferred nasal dilator of this inventionwith a partial peel back view of the adhesive layer;

FIG. 3: is a side elevation, cross-sectional, exploded view of the nasaldilator of FIG. 2;

FIG. 4: is a top planar view of a preferred resilient member, includingthe periphery of the substrate of the nasal dilator in phantom;

FIG. 5: is a top planar view of an alternative resilient memberconsisting of a reinforcing scrim also depicting the periphery of thesubstrate in phantom;

FIG. 6: is a top planar view of a preferred nasal strip of thisinvention with a partial peel-back view of the adhesive layer; and

FIG. 7: is a side elevation, cross-sectional, exploded view of the nasalstrip of FIG. 6.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides adhesively-applied nasal strips and dilators andmethods for substantially preventing a nasal wall tissue of a nose fromdrawing in during breathing. As used herein, the following terms aredefined:

-   -   “aromatic medication” refers to therapeutic substances and        compounds which can be consumed by inhaling through the nose,        such as a medicated vapor or gas, which have potential or        demonstrated efficacy in helping patients breath easier or        better;    -   “medicated” and “medicine” will be used broadly to connote the        inclusion of any of a variety of treatments including aromatic,        topical and transdermal medicines, anti-viral, anti-microbial or        anti-bacterial agents, scents, salves and other therapeutic        substances which might be desirable on tissues as discussed        herein;    -   “neat” refers to a fragrance either in its undiluted or unused        condition. It can refer to the fragrance on a dilator strip as        it is packaged and ready for a wearer to apply to his or her        skin, or it can be used to define a relatively pure fragrance        prior to add/mixing other fragrances and/or substances.    -   “in-use” refers to use by a patient or a consumer in its        commercially-intended fashion;    -   “extended release” refers to a group of substances, compounds,        and/or devices useful for sustained release of fragrances to        increase either the neat or in-use olfactory effectiveness or        useful life.    -   “fragrance oil” refers to the numerous known oil-based scents,        their homologues, derivatives and chemical variations.    -   “body activated” means that the activity of the cosmetic        fragrance, aromatic or transdermal medication increases when        applied to the body. This can be accomplished by means of pH,        heat or perspiration activation, for example.    -   “fragrance notes” means fragrance ingredients blended or in neat        form which achieve “top”, “middle”, or “bottom” note components.        The first is a refreshing quality sensed upon application. The        last is the essence of the fragrance which stays with the wearer        for a long time. The middle note is the perceived quality that        bridges from top to bottom note. These materials themselves are        each classified with respect to the aromas given off, as to        providing a green note, floral note, aldehidic note, fruity        note, chypre note, oriental note, leather note, tobacco note,        etc.    -   “dual fragrance delivery system” refers to either dual notes, or        dual delivery mechanisms for extending the olfactory        effectiveness of fragrances and aromatic medications. Such        delivery mechanisms include, for example, fixatives, gels,        starches, microcapsules, fragrance carriers, pH sensitive        compounds, waxy substances, polymers, cyclodextrins, cellulose,        and variations thereof.

Nasal Dilator

With reference to the figures and in particular, FIGS. 1-3 thereof,there is shown a preferred nasal dilator 100 sized to fit across thenose of the wearer so as to engage the outer wall tissue of the left andright nasal passages of the wearer. As shown in FIGS. 2-3 the nasaldilator 100 includes an elongated substrate 30 having a pair oflongitudinal sides, a pair of transverse ends and top and bottomsurfaces thereon. Disposed on a bottom surface of the substrate 30 is anadhesive layer 32 for permitting easy attachment to the wearer's skin.Also attached to the substrate is a resilient member 60 which provides agentle expanding force to the nasal wall tissue when the dilator isadhesively attached to the nose. Finally, an aromatic substance 50 isdisposed on a portion of the dilator so as to be inhaled through thenose of the wearer during breathing. Additionally, a transdermalsubstance can be added to the bottom surface of the dilator 100, with,or without an aromatic substance, such as a fragrance or aromaticmedication.

In further embodiments of this invention, the dilator 100 can include abacking layer 40. The backing layer 40 and resilient member 60 aredesirably bonded to the substrate 30 using pressure sensitive adhesivelayers 42 and 62. As shown in FIG. 3 the aromatic substance 50 can bedisposed on any surface of the dilator 100. Preferably the aromaticsubstance 50 is disposed on an absorbent layer portion of the dilator100. The absorbent layer portion can be a separate absorbent layer or aportion of the elongated substrate 30 or backing layer 40, for example.Alternatively, the aromatic substance 50 can be disposed in one of theadhesive layers in an admixture or segregated form, such as in aseparate bottom layer location, or contained within fragrance carriers,microcapsules, or coatings, for example. Finally, a release paper strip10, such as silicone or wax coated kraft paper, can be added over thepressure sensitive adhesive layer 32 prior to packaging the dilator 100for sale.

The elongated substrate 30 of this invention may include any thin,flexible, breathable material for maximizing comfort. Preferably thismaterial permits the passage of air and moisture vapor, such asperspiration, but inhibits the passage of dirt and liquid perspirationor rain water, etc. The elongated substrate can include, for example, awoven or non-woven fabric material, such as non-woven, polyester fabric.One good example is a fabric produced by DuPont E. I. de Nemours & Co.,Inc. under the trademark Sontara®. Alternatively, the elongatedsubstrate 30 can include a thermoplastic woven or non-woven fabric, suchas spun-bonded, or melt-blown, polyethylene or polypropylene fibers,which in sufficient-thickness can be “self-resilient,” or capable ofgently opening nasal passage ways when adhesively applied to exteriornasal tissue, as discussed in more detail below. The substrate 30 canalso be treated with the aromatic medication 50 of this invention, alongwith a hydrophilic or hydrophobic additive for absorbing or repellingsweat or moisture on a selective basis.

Attached to the substrate 30 on the nose skin-facing side, or bottomsurface, of the substrate 30 is an adhesive layer 32. This adhesivelayer, along with optional adhesive layers 62 and 42 can be made of apressure sensitive, hypoallergenic, biocompatible adhesive material. Asused herein, “pressure-sensitive” refers to any releasable adhesive orreleasable tenacious means. Adhesive compositions suitable for nasaldilators and nasal strips include water-based pressure-sensitiveadhesives, such as acrylate adhesives, thermoplastics “hot melt”adhesives, two-sided adhesive tape, elastomer-based adhesives, andacrylic adhesives. Good examples include polyacrylate adhesive,polyvinylethyl ether blend adhesive, and 3M1509 double-sided medicaltape provided by 3M Inc., St. Paul, Minn. The 3M product is adouble-sided transparent polyethylene film, coated on both sides with ahypoallergenic, pressure-sensitive acrylate adhesive, supplied on apaper liner. Of course, adhesive layers 62 and 42 need not be apressure-sensitive type at all, since once the resilient member 60 andbacking layer 40 are adhered to the substrate 30, it is undesirable forthese layers to separate during application or removal of the dilatorfrom the nose.

The resilient member 60 of this invention preferably includes one ormore spring strips 60 a which can be die-cut from spring ribbonmaterial. Good examples of spring ribbon material include biaxiallyoriented polyester that is approximately 0.01-0.15 inches thick, butpolyethylene or polypropylene strips of like or greater thickness wouldalso provide expanding force to the dilator 100.

Although both an elongated substrate 30 and resilient member 60 aredisclosed, there is no reason why the functions of these members cannotbe performed by a single elongated resilient member, or layer,comprising a flexible, but spring-like, woven oriented layer, non-wovenlayer, scrim, ribbon composite or sheet material. For example, anon-woven web of melt-blown or spun-bonded fibers of polyethylene orpolypropylene, cut into a strip of about 0.01-0.15 inches thick by about2-4 inches in length would transmit air and perspiration vapor easily,and would also provide a spring force to gently open nasal openings whenadhesively applied to a nose. Alternatively, as shown in FIG. 5, aresilient layer, such as scrim 60 b can be disposed within, orsubstantially along the perimeter 11 of the substrate 30 or outerperipheral region of the dilator 100.

Fiber additions to the resilient member 60, such as, glass, graphite,resin, carbon or boron will also improve resiliency. Resin fibers caninclude a variety of thermoplastic or thermosetting polymers. Good fibercandidates include, for example, nylon, polyethylene, and polyesterfibers, for example SPECTRA or COMPET fibers sold by Allied SignalCorp., Kevlar® 29, 49 or 149 aramid fibers sold by DuPont, glass, suchas E-glass and S-Glass fibers, graphite fibers, carbon fibers, boronfibers, or combinations of these fibers.

The resilient member, whether including spring strips 60 a or aresilient scrim 60 b or woven, non-woven, or solid film sheet layer (notshown) is preferably joined together in a webbing operation either bymelt bonding, adhesive bonding or ultrasonic bonding. In conventionaloperations, a ribbon of resilient material and substrate material areadhesively joined together as they are fed into an overlapping positionin a die or roller. Adhesive layers 42 and 62 are used to join thebacking layer, resilient member 60 and elongated substrate 30 togetherprior to die-cutting to form the final periphery 11 of the dilator 100.The adhesive layers 42, 62 and 32 can be applied by spray, roll orknife, as is customary in the web-processing industry.

An important advantage of the resilient layer, such as scrim 60 b or asheet layer, as opposed to a pair of discrete spring strips 60 a of thisinvention, is the elimination of a careful placement operation prior todie-cutting. Such an expensive step becomes unnecessary, since theresilient layer preferably conforms generally to the perimeter 11 of thefinal die-cut dilator. This can eliminate waste and minimize much of theexpense of the webbing operation. It also provides for a more uniformspring action along most or all of the surface area of the dilator 100.

Additionally, this invention contemplates employing thermoplasticmaterials in the backing layer 40 and substrate 30, and alternatively,with respect to the resilient member 60 or layer. When thermoplasticmaterials are used, this invention enables inexpensive melt-bonding ofthe layers of material, with heat and pressure, to provide a compositenasal dilator structure. Melt-bonding could eliminate the need ofadditional adhesive layers 42 and 62 and provide a greater structuralintegrity to the dilator no matter what form of resilient member isemployed. However, a woven layer, non-woven layer or resilient scrim 60b would ideally be suited for thermoplastic bonding of layers sincethese materials have pores for permitting softened thermoplasticmaterial to bond between the fibers or filaments, further increasing thestrength of the dilator 100.

Nasal Strip

As illustrated in FIGS. 6 and 7, there is further shown a nasal strip200 which includes an elongated substrate 230, which may be a flexiblefabric-like member, as discussed above for elongated substrate 30, or aresilient member which is self-resilient, and can permit a gentleexpanding force to a nasal tissue when it has adhesively attached to anose. In the preferred embodiment, however, the nasal strip 200 ismerely a tape-like means for delivering a cosmetic fragrance, aromaticmedication or transdermal medication. Fragrances and medications,hereinafter “active ingredient(s)”, can be disposed in the elongatedsubstrate 230, such as by absorption of active ingredients 250 into afabric or pores of an absorbent layer, or by coating a top or bottomsurface of one layer of the nasal strip 200, such as the elongatedsubstrate 230.

Preferably the active ingredient 250 is separated by a separate layer,or layer portion, from the adhesive layer 232 facing the skin of thewearer, such as defined by dimension “(a)” in FIG. 7. This has theadvantage of permitting neat fragrances, such as volatile oils, to bedisposed onto the top of the elongated substrate 230 without risking thepolymerization of the pressure-sensitive adhesive 232.

Alternatively, the elongated substrate 230, itself, can be made of aliquid or oil-resistant material, or treated to be hydrophilic on oneside. Good examples include a woven or non-woven layer of thermoplasticor thermosetting fibers, or a solid thermoplastic or thermosetting film,which will enable an active aromatic ingredient to be disposed on anopposite planar surface from the pressure-sensitive adhesive 232, so asto keep them separate and minimize polymerization of the adhesive.Alternatively, as will be described below, fragrance oils andmedications can be disposed within a fragrance delivery mechanism, suchas a carrier 260. Although the carrier-entrapped oil or medication canbe disposed anywhere on the substrate 230, the inherent property of mostcommercial carriers permit them to be disposed within the adhesive layer232 without substantially mixing with the degradable polymers of theadhesive. Alternatively, microcapsules can be used in this fashion.Attached over the pressure-sensitive adhesive layer is a preferredrelease paper strip 210, similar to release paper strip 10.

The above nasal strip 200 can be modified by applying a 2-sided medicaltape, such as the previously disclosed 3M1509 tape, or barrier layer ofabout 0.025-0.125 mm of an occlusive polyethylene film, such asdisclosed in U.S. Pat. No. 4,880,690 to Szycher, and hereby incorporatedby reference. A thermoplastic or thermosetting layer can separate thepressure-sensitive adhesive 232 and any fragrance oils or liquidmedications in neat form which absorb through the substrate 230.

It is understood that these techniques have equal utility in thefabrication of nasal dilators. If the separating, thermoplastic orthermosetting film or fabric is of sufficient thickness, and tensilestrength, it could also provide a resilient force for helping to gentlyopen nasal passageways when adhesively applied to a nose. This couldpermit the use of a single layer to accomplish two functions, and helpto reduce costs.

Fragrances and Aromatic Medications

Fragrance formulation is an art in which the senses of the skilledperfumer are more important than chemical analysis. A fragrance resultsfrom a variety of components or ingredients in a fragrance composition.Ordinarily, fragrances are created by blending materials comprisingodoriferous essential oils, extracts from woods, gums, flowers and otherbotanicals, resins, animal secretions, and synthetic aromatic materials.These materials are blended in order to achieve what is known as top,middle and bottom notes. (See previous definition.)

Suitable fragrance compounds and compositions for this invention aredisclosed in U.S. Pat. No. 4,145,184, Brain and Cummins, issued Mar. 20,1979; U.S. Pat. No. 4,209,417, Whyte, issued Jun. 24, 1980; U.S. Pat.No. 4,515,705, Moeddel, issued May 7, 1985; and U.S. Pat. No. 4,152,272,Young, issued May 1, 1979, all of said patents being incorporated hereinby reference.

Fragrances can be classified according to their volatility. The highlyvolatile, low boiling, ingredients typically have boiling points ofabout 250° C. or lower. The moderately volatile ingredients are thosehaving boiling points of about 250° C. to about 300° C. The lessvolatile, high boiling, ingredients are those having boiling points ofabout 300° C. or higher. Many of the fragrance ingredients as discussedhereinafter, along with their odor and/or flavor characters, and theirphysical and chemical properties, such as boiling point and molecularweight, are given in “Perfume and Flavor Chemicals (Aroma Chemicals)”Steffen Arctander, 1969, incorporated herein by reference.

Examples of the highly volatile, low boiling, fragrance ingredients,also called “top notes,” are: anethole, benzaldehyde, benzyl acetate,benzyl alcohol, benzyl formate, iso-bornyl acetate, camphene, cis-citral(neral), citronellal, citronellol, citronellyl acetate, para-cymen,decanal, dihydrolinalool, dihydromyrcenol, dimethyl phenyl carbinol,eucalyptol, geraniol, geraniol, geranyl acetate, geranyl nitrile,cis-3-hexenyl acetate, hydroxycitronellal, d-limonene, linalool, linaooloxide, linalyl acetate, linalyl propionate, methyl anthranilate,alpha-methyl ionone, methyl nonyl acetaldehyde, methyl phenyl carbinylacetate, laevomenthyl acetate, menthone, iso-menthone, myrcene, myrcenylacetate, myrocenol, nerol, neryl acetate, nonyl acetate, phenyl ethylalcohol, alpha-pinene, beta-pinene, gamma-terpinene, alpha-terpineol,beta-terpineol, terpinyl acetate, and vertenex (para-tertiary-butylcyclohexyl acetate). Some natural oils also contain large percentages ofhighly volatile ingredients. For example, lavandin contains as majorcomponents: linalool; linalyl acetate; geraniol; and citronellol. Lemonoil and orange terpenes both contain about 95% of d-limonene.

Examples of moderately volatile fragrance ingredients, also called“middle notes,” are: amyl cinnamic aldehyde, iso-amyl salicylate,beta-caryophyllene, cedrene, cinnamic alcohol, coumarin, dimethyl benzylcarbinyl acetate, ethyl vanillin, eugenol, iso-eugenol, flor acetate,heliotropine, 3-cis-hexenyl salicylate, hexyl salicylate, lilial(para-tertiarybutyl-alpha-methyl hydrocinnamic aldehyde), gamma-methylionone, nerolidol, patchouli alcohol, phenyl hexanol, beta-selinene,trichloromethyl phenyl carbinyl acetate, triethy Icitrate, vanilla andveratraldehyde. Cedarwood terpenes are composed mainly of alpha-cedrene,beta-cedrene, and other C₁₅H₂₄ sesquiterpenes.

Examples of the less volatile, high boiling, perfume ingredients,referred to as “bottom notes,” are: benzophenone, benzyl salicylate,ethylene brassylate, galaxolide(1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl-cyclopenta-gama-2-benzopyran),hexyl cinamic aldehyde, lyral (4-(4-hydroxy4-methylpentyl)-3-cyclohexene-10-carboxaldehyde), methyl cedrylone, methyldihydro jasmonate, methyl-beta-naphthyl ketone, musk indanone, muskketone, musk tibetene, and phenylethyl phenyl acetate.

The fragrance employed in the nasal strips and dilators of the presentinvention can also comprise a cooling agent or a combination of coolingagents. See U.S. Pat. No. 5,725,865 to Mane et al., hereby incorporatedby reference. Cooling agents are compounds which directly effect thosenerve endings responsible for hot or cold sensations. In this sense,they are deemed to be medications. Suitable cooling agents are menthol,menthol-based or acyclic carboximides, and menthol-based or acyclicketals (acetals). Suitable cooling agents useful in the presentinvention include: monomenthyl succinate and its alkali metal salts andalkaline earth derivatives, 3-1-menthoxypropane-1,2-diol,N-substituted-p-menthane-3-carboxamides and acyclic carboxamides andmixtures thereof, as disclosed in U.S. Pat. No. 5,622,992 to Beck, andhereby incorporated by reference.

Additional cooling agents include, for example, 3-1-menthoxy propane1,2-diol, which is fully described in detail in U.S. Pat. No. 4,459,425,issued Jul. 10, 1984 to Amano et al., incorporated herein by referencein its entirety. This volatile aromatic is commercially available, asTK-10 from Takasago Perfumery Co., Ltd., Tokyo, Japan.

The N-substituted-p-menthane-3-carboxamides cooling agents are fullydescribed in U.S. Pat. No. 4,136,163 to Watson et al., issued Jan. 23,1979 incorporated herein by reference in its entirety. Preferred coolingagents of this class include N-ethyl-p-menthane-3-carboxamide, which iscommercially available as WS-3 from Wilkinson Sword Limited.

Useful acyclic carboxamides are fully described in U.S. Pat. No.4,230,688 to Rowsell et al., issued Oct. 28, 1980 incorporated herein byreference in its entirety. The most preferred cooling agent of thisclass is N,2,3-trimethyl-2-isopropylbutanamide which is commerciallyavailable as WS-23 from Wilkinson Sword Limited.

Preferred for use herein is a mixture of 3-1-menthoxy propane 1,2-diol,N-ethyl-p-menthane-3-carboxamide andN,2,3-trimethyl-2-isopropylbutanamide.

Various other non-active, aromatic components (e.g., aldehydes andesters) may also be used to impart fruit scents. These aromaticsinclude, for example, benzaldehyde (cherry, almond); citral (lemon,lime); neral; decanal (orange, lemon); aldehyde C-8, aldehyde C-9 andaldehyde C-12 (citrus fruits); tolyl aldehyde (cherry, almond);2,6-dimethyl-octanal (green fruit); and 2-dodecenal (citrus, mandarin).Mixtures of these aromatics can also be used.

Preferred examples of aromatic medications of this invention includecamphor, ephedrine, eucalyptus oil, peppermint oil, menthol, methylsalicylate, bornyl acetate, lavender oil, or a combination of these.Menthol, because of therapeutic benefits which extend beyond itspeppermint smell, is especially attractive as an antitussive, coolingagent and decongestant.

These and other aromatic active components are more fully described in53 Federal Register 30561, Aug. 12, 1988, incorporated by referenceherein.

Other Pharmaceutical Active Ingredients

Other pharmaceutical actives useful in the present invention include anychemical material or compound suitable for topical administration;however, such drugs should avoid interfering with the stability of theadhesive composition, if added thereto. Such substances include, but arenot limited to antibiotics, wound healing agents, vasodilators,coagulants, birth control drugs, cardiovascular drugs, chemotherapeuticagents, vitamins, antiviral agents, anti-microbial agents, analgesics,anti-inflammatory agents, such as steroidal agents, such ashydrocortisone and triamcinolone, or non-steroidal agents, such asibuprofen, naproxen, flufenamic acid, mefenamic acid, meclofenamic acid,prioxicam and felbinac. Transdermal decongestants and antihistamines arealso available, such as diphenhydramine and triprolidine transdermalantihistamine, available from Proctor and Gamble Co., Inc., Cincinnati,Ohio; others include ephedrine (which can also be an aromatic),dimethindene, epinastine, emedastine, and clonidine. Transdermalsubstances can be delivered in a number of known manners.

Useful anesthetic or antipruritic drugs are selected from the groupconsisting of lidocaine, lidocaine hydro-chloride, bupivacainehydrochloride, chloroprocaine hydrochloride, dibucaine hydrochloride,etidocaine hydrochloride, mepivacaine hydrochloride, tetracaine,tetracaine hydrochloride, dyclonine hydrochloride and hexylcainehydrochloride, benzocaine, benzyl alcohol, butamben picrate, camphor(also an aromatic active), camphorated metacresol, dibucaine, dibucainehydrochloride, dimethisoquin hydrochloride, diphenhydraminehydrochloride, juniper tar, menthol (also an aromatic medication),phenol, phenolate sodium, promazine hydrochloride, resorcinol andmixtures thereof.

Vitamins

Various vitamins may also be included in the topical compositions of thepresent invention. For example, Vitamin A, and derivatives thereof,ascorbic acid, Vitamin B, biotin, pantothenic acid, Vitamin D, andmixtures thereof may be used. Vitamin E, tocopherol acetate andderivatives may also be used.

These topical, aromatic and transdermal substances and medications canbe added to the substrate 30, resilient member 60, mixed within adhesivelayers 62, 42 or 32, as in, for example, a dispersion-type transdermalpatch formulation made from acrylate copolymer adhesive, a lecithin gelbased matrix, or a polyurethane acrylic copolymer, such as disclosed inU.S. Pat. No. 4,638,043 to Szycher et al., which is hereby incorporatedby reference. Alternatively, a rate controlling membrane could be used,such as Eudragit RL-100. Further delivery mechanisms will now bedisclosed.

Fragrance Delivery Systems and Mechanisms

There are several preferred methods of distributing one or more cosmeticfragrance or aromatic medicinal components throughout the strips anddilators of this invention. Such methods are herein referred to as“fragrance delivery systems” or “mechanisms.” Such mechanisms includefixatives, such as floral and botanical absolutes, concretes, andresinoids, animal secretions and extracts, macrocyclic musks, polycyclicmusks, nitromusks, glucoside polyols, galaxolide, ethylene brassylate,acetylhexamethyl tetralin, and like compositions disclosed in U.S. Pat.No. 5,380,707 to Barr et al. and U.S. Pat. No. 3,045,047 to Davidson etal., which are hereby incorporated by reference.

Another mechanism is a pure method wherein a liquid fragrance ormedicinal component is absorbed or blended directly into the substrate,resilient member, or adhesive layers (“nasal product components”) in anolfactory effective amount. See U.S. Pat. No. 3,655,129 to Seiner andU.S. Pat. No. 3,688,985 to Engel, which teach slow release fragrantfilms.

Other mechanisms, include gels, such as gelled cellulose triacetate(U.S. Pat. No. 3,846,404 to Nichols), polyvinyl acetal resin gelled withoxygenated terpene, (U.S. Pat. No. 3,954,963 to Kuderna) and polymericcarbohydrate derivatives (U.S. Pat. No. 4,067,824 to Teng et al.); saidpatents hereby incorporated by reference.

Another method is by using a carrier or an encapsulation, whereby thefragrance or medicinal component is contained in microcapsules, orporous carriers, such as cellulose or hydrophilic porous organic orinorganic particles, which are then mixed within a nasal productcomponent. The carrier or encapsulation method embodiment can provide a“controlled or extended release” of the fragrance or medicinal componentas well as extending the user's exposure to the fragrance or medicinalcomponent after transfer to the skin. Adhesive may be used to hold thecarriers or microcapsules on a substrate prior to transfer, or they canbe disposed between layers or on the exterior top surface of thepreferred strips and dilators.

There are several well known types of encapsulation that may be selectedto provide a controlled release of a fragrance or medication in thepresent invention. For example, two suitable types of encapsulationinclude: (a) microcapsules that rupture, by contact pressure, or bypartly or completely dissolving in water or perspiration, at the pointof use so that the fragrance or medicinal component is transferred tothe user's skin, (b) microcapsules that continually effuse the fragranceor medicinal component without rupturing, (c) multiphase capsules, suchas those disclosed in U.S. Pat. No. 3,909,444 to Anderson et al., whichinclude a water-soluble polymeric active within a liquid permeable,water-insoluble capsule wall, for example; and (d) microcapsules whichare capable of re-encapsulation, as in, for example, when perspirationevaporates, as disclosed in U.S. Pat. No. 5,711,941 to Behan et al.,said patents hereby incorporated by reference. Behan et al. discloses anumber of self-emulsifying film-forming substances, like waxy starchesand modified starches sold under the trade names N-Lok and Purity Gum BEavailable from National Starch and Chemical Co.

Microcapsules that rupture at the point of use provide improved cold andallergy relief and shelf life, because the fragrance or medicinalcomponent generally cannot be dissipated until the microcapsule ruptureswhen the therapeutic substance is transferred onto the user's nasal walltissue. Microcapsules that continually effuse an active ingredientwithout rupturing, and porous carriers, also provide improved cold andallergy relief and shelf life, because the medicinal component isretained within partially open microcapsules, or within the pores ofcarriers, which allows the fragrance or medicinal component tocontinually effuse over a predetermined time period. The fragrance ormedicinal component in this type of capsule or carrier dissipates at acontrolled, generally more uniform rate and provides continual, longerlasting, and more reliable or defined benefits to the user. As will beunderstood by those skilled in the encapsulation art, suitableencapsulation technologies include coacervation, prilling,microsponging, and spray drying. Examples of preferred specificencapsulation products include those sold under the name Polyiff, asavailable from International Flavor and Fragrances, and IN-CAP asavailable from Polak Frutal Works Micro.

The fragrance carriers employed in the compositions of the presentinvention preferably comprise hydrophilic particles having a diameter offrom about 0.001 micron to about 50 microns, preferably from about 0.01to about 20 microns, more preferably from about 0.1 to about 10 microns.As used herein, a “hydrophilic carrier particle” means a particle whichentraps a fragrance (e.g., perfume oil or medication) in the dry (e.g.,neat) nasal product and releases entrapped fragrance when the product isused, for example, when contacted by finger pressure or perspiration.

One type of inorganic carrier suitable for use in the present inventionincludes amorphous silica, precipitated silica, fumed silica, activatedcarbon, and aluminosilicates such as zeolite and alumina with a porevolume of at least 0.1 ml/g consisting of pores with a diameter between4 and 100 A, which by their nature, are hydrophilic. Preferably,amorphous silica gel is used because of its high oil absorbency. Silicagel particles include SyloidR silicas such as Numbers: 72; 74, 221, 234;235; 244; etc. SyloidR silicas are available from W. R. Grace & Co.,Davison Chemical Division, P.O. Box 2117, Baltimore, Md. 21203. Suchparticles have surface areas of from about 250 to about 340 m²/g; porevolumes of from about 1.1 to about 1.7 cc/g; and average particle sizesof from about 2.5 to about 6 microns. Fumed silica particles haveprimary particle diameters of from about 0.007 to about 0.025 micron andinclude Cab-O-SilR Numbers: L-90; LM-130; LM-5; M-5; PTG; MS-55; HS-5;and EH-5. Cab-O-SilR silicas are available from Cabot Corp., P.O. Box188, Tuscola, Ill. 61953. It is preferred that there be only minimalamounts of other materials present when the fragrance is added to thesilica particles to maximize absorption. It is especially preferred thatonly small amounts, e.g., less than about 10% of organic materials,including waxes, be present in the admixture during fragranceabsorption.

Another type of carrier suitable for use in the present inventionincludes cyclodextrin. As used herein, the term “cyclodextrin” (CD)includes any of the known cyclodextrins such as unsubstitutedcyclodextrins containing from six to twelve glucose units especially,alpha-, beta-, gamma-cyclodextrins, their derivatives, and mixturesthereof, that are capable of forming inclusion complexes with fragranceingredients. Alpha-, beta-, and gamma-cyclodextrins can be obtainedfrom, among others, American Maize-products Company (Amaizo), CornProcessing Division, Hammond, Ind.; and Roquette Corporation, Gurnee,Ill. There are many derivatives of cyclodextrins that are known.Representative derivatives are those disclosed in U.S. Pat. No.3,426,011, Parmerter et al., issued Feb. 4, 1969; U.S. Pat. Nos.3,453,257, 3,453,258, 3,453,259 and 3,453,260, all in the names ofParmerter et al., and all issued Jul. 1, 1969; U.S. Pat. No. 3,459,731,Gramera et al., issued Aug. 5, 1969; U.S. Pat. No. 3,553,191, Parmerteret al., issued Jan. 5, 1971; U.S. Pat. No. 3,565,887, Parmerter et al.,issued Feb. 23, 1971; U.S. Pat. No. 4,535,152, Szejtli et al., issuedAug. 13, 1985; U.S. Pat. No. 4,616,008, Hirai et al., issued Oct. 7,1986; U.S. Pat. No. 4,638,058, Brandt et al., issued Jan. 20, 1987; U.S.Pat. No. 4,746,734, Tsuchiyama et al., issued May 24, 1988; and U.S.Pat. No. 4,678,598, Ogino et al., issued Jul. 7, 1987, U.S. Pat. No.4,356,115, Shibanai et al., issued Oct. 26, 1982, all of said patentsbeing incorporated herein by reference. Examples of cyclodextrinderivatives suitable for use herein are methyl-β-CD, hydroxyethyl-β-CD,and hydroxypropyl-β-CD of different degrees of substitution (D.S.),available from Amaizo and from Aldrich Chemical Company, Milwaukee, Wis.Water-soluble, e.g., perspiration dissolving, derivatives containingsugar-type, or dextrine molecules, and derivatives, are also highlydesirable.

The fragrance oils, medications, carriers and capsules comprising thefragrances of the present invention can be incorporated into adhesives,substrates, and resilient members as is or they can be encapsulated in,for example, waxy materials, such as fatty acids, and then added tothese nasal product components. To impregnate the fragrance within thefragrance carrier, the fragrance and the carrier are mixed togetherunder shear conditions to provide a homogeneous mixture.

If it is desired to encapsulate the fragrance oil, medications,fragrance carrier or capsules (double encapsulation), the preferredcoating materials include both water-insoluble and water-solublematerials, typically selected from waxy materials such as paraffinicwaxes, microcrystalline waxes, animal waxes, vegetable waxes, saturatedfatty acids and fatty alcohols having from 12 to 40 carbon atoms intheir alkyl chain, and fatty esters such as fatty acid triglycerides,fatty acid esters of sorbitan and fatty acid esters of fatty alcohols,or from both water-insoluble and water soluble polymers. Typicalspecific suitable waxy coating materials include lauric, myristic,palmitic, stearic, arachidic and behenic acids, stearyl and behenylalcohol, microcrystalline wax, beeswax, spermaceti wax, candelilla wax,sorbitan tristearate, sorbitan tetralaurate, tripalmitin, trimyristinand octacosane. A preferred waxy material is coconut fatty acid. Waxymaterials that melt, or substantially soften, at about 98.6° F., orgreater, for fragrance activation upon exercise, exertion or fever,would be ideal for nasal dilators and strips.

Examples of polymeric materials which can be used for the coating of thefragrances, medications, carriers, and microcapsules, herein arecellulose ethers, such as ethyl, propyl or butyl cellulose; celluloseesters such as cellulose acetate, propionate, butyrate oracetate-butyrate; ethylene-vinyl acetate copolymer; polyalkylene glycolsuch as ethylene, propylene, tetramethylene glycol; urea-formaldehyderesins, polyvinyl alcohol, polyvinyl chloride, polyvinylidene chloride,polyethylene, styrene, polypropylene, polyacrylates, polymethacrylates,polymethylmethacrylates and nylon. Such materials and their equivalentsare described in greater detail in any conventional handbook ofsynthetic organic plastics, for example, in Modern PlasticsEncyclopaedia volume, Vol. 62, No. 10A (for 1985-1986) at pages 768-787,published by McGraw-Hill, New York, N.Y. (October 1985), incorporatedherein by reference. A preferred polymeric material is ethyl cellulose.The polymeric coating materials can be plasticized with knownplasticizing agents such as phthalate, adipate and sebacate esters,polyols (e.g., ethylene glycol), tricresyl phosphate, castor oil andcamphor. These polymeric coatings are preferred for the superiorprotection they provide.

The coating material can comprise a mixture of waxy materials andpolymeric coating materials. The function of the coating which surroundsthe fragrances and/or medications is to provide further improvedstability, as well as to allow for dual delivery of active ingredientswherein different active ingredients can be impregnated in differentdelivery mechanisms to achieve: extended release, prolonged olfactoryeffectiveness, different neat and in-use scents or actives, andminimization of olfactory saturation.

In addition to the fragrances incorporated in coatings andmicrocapsules, or impregnated within a fragrance carrier, thecompositions of the present invention can also optionally containfragrances present in their liquid form (e.g., not impregnated within afragrance microcapsule carrier). Incorporating a liquid fragrancecomposition into the nasal dilators and strips herein can contribute tounique fragrance impressions. For example, a nasal strip which containsboth a fragrance impregnated within a fragrance carrier and a liquidfragrance can 1) give a dual fragrance impression (e.g., can exhibitdifferent fragrance impressions for the dry (neat) strip versus thein-use strip), or 2) can optimize the fragrance impression for both theneat strip and the in-use strip.

The fragrances which can be used as neat fragrances for the nasaldilators and strips of the present invention are the same as thosehereinbefore described above.

According to the dual fragrance improvements of the invention, thefragrance elements of the composition are of distinct olfactive natureand the only combination criterion resides in the harmonious effectdeveloped by them. See U.S. Pat. No. 5,723,420 to Wei et al., herebyincorporated by reference. In a preferred embodiment of the compositionwhich comprises two fragrance elements, one of said elements is of aheavier odor character or lower note than the other. Thus, a fragranceingredient which develops a cooling menthol odor may harmonize well withan element having a musky, heavier odor. As a result, it could besuggested to combine the second of these ingredients in liquid orcarrier form with the first in microencapsulated form. The user wouldthen be exposed to a first impression of woody-amber scent which wouldbe followed, upon the activation resulting from rupture of themicrocapsules during perspiration, or simply from contact, with atingling menthol sensation for example.

In these applications, the above-mentioned embodiment of the fragrancecomposition wherein the micro-encapsulated ingredient is of a lighterodor character than the liquid perfuming element, turns out to beparticularly advantageous for preserving the volatile high notes, suchas menthol and camphor, until they are most needed. It is clear,however, that other combinations of odor characters and deliverymechanisms can be used. For example, one could use a relativelytenacious perfuming element of a baby powder character, in liquid form,combined with a micro-encapsulated element of a fresh citrus, menthol,or lavender odor, which would provide a fresh, sporty olfactive impulsefollowing a surge of perspiration. Or, a child formulation using acherry character, liquid benzaldehyde, with a micro-encapsulated coolingagent, WS-23 or menthol, and a micro-encapsulated analgesic andephedrine, which are both activated by elevated body temperature orperspiration, during a fever. Another desirable combination of activeagents includes a transdermally effective amount of an analgesic andanti-inflammatory agent, such as ibuprofen, with about 5-10 mg ofmicroencapsulated or carrier impregnated aromatic menthol oil andcamphor. As previously mentioned, the combination of two distinctdelivery mechanisms, olfactive characters, and/or medications, is almostlimitless, and preferably includes two or more fragrances and/ormedications, using the same, or different, delivery mechanisms,depending on the desired effect, and end-use.

This invention also employs a fragrancing composition having fragrancingcomponents that are not activated until they are to the skin of a human,e.g., “body activation.” See U.S. Pat. Nos. 5,626,552 and 5,378,468which teach pH activation of fragrances, and are hereby incorporated byreference. One preferred composition for achieving this result isalkaline or (if anhydrous) capable of producing an alkaline pH when incontact with water, prior to application, and includes (1) a vehiclesuch that when the composition is in contact with water, prior toapplication, the composition is at an alkaline pH; and (2) at least onepotential fragrance that is at least one compound having little or noodor in the alkaline composition but which can be hydrolyzed in a lowerpH environment to produce compounds having a relatively strong aroma.Upon application of the alkaline composition to the skin surface, thestrong buffering capacity of the skin (the surface of which has a normalpH of 5.5-7.0) neutralizes alkalinity of the composition (lowers pH) soas to restore normal skin surface pH; the potential fragrance is thenhydrolyzed at the lower pH to release the compound having relativelystrong aroma. The potential fragrance or medicinal composition can beincorporated as a component of a nasal dilator strip, the fragrance ormedicinal composition being released after application to the body.

Dosage

Those skilled in the art can determine the quantity of cosmeticfragrance or therapeutic substance to be applied to any given area ofthe substrate according to the type of fragrance or medicine to beapplied and the end-use application (sports, snoring, cold-relief,adult, child, etc.). Factors to be considered include the cost of thetherapeutic substance, its physical characteristics, the quantity whichshould be applied to the nasal skin to accomplish the particular goal ofthe application (e.g., soothing, protecting, relieving cold and allergysymptoms, providing a cooling sensation during a workout, etc.) and thecost and convenience of packaging. The preferred level of cosmeticfragrance or therapeutic substance is from about 0.1 mg to about 10 mgper cm² of skin depending on the substance and end use application.

Fragrances, in neat, carrier or microcapsule form, vitamins, therapeuticand medicated substances, and coated fragrances can be applied tosubstrates, adhesives and resilient layers of this invention by anyconvenient technique such as spraying, dipping, padding, or, in the caseof the preferred substances, by spraying, rolling, dipping or extrusionof the oil or melted substances onto a moving web of substrate orresilient layer material.

From the foregoing, it can be realized that this invention providesimproved therapeutic delivery systems which include medications and/orfragrances having improved delivery characteristics, greater resistanceto olfactory saturation, and greater shelf life and in-useeffectiveness. They also, optionally, reduce adhesive residue andimprove upon the therapeutic delivery of aromatic medications. Thedilators and methods of this invention are useful for helpingindividuals with deviated septums and athletes who desire more oxygenduring a performance. Although various embodiments have beenillustrated, this is for the purpose of describing, but not limiting theinvention. Various modifications which will become apparent to oneskilled in the art, are within the scope of this invention described inthe attached claims.

1. A therapeutic delivery system comprising a plurality of multiphasecapsules, said multiphase capsules containing first and secondtherapeutic agents disposed in separate phases within said multiphasecapsules to deliver said first and second therapeutic agents by at leasttwo different delivery mechanisms.
 2. The therapeutic delivery system ofclaim 1 wherein said first therapeutic agent is delivered by a topicaladministration, and said second therapeutic agent is delivered by amechanism which is not topical administration.
 3. The therapeuticdelivery system of claim 1 wherein said first therapeutic agentcomprises one or more of: antibiotics, wound healing agents,vasodilators, coagulants, birth control drugs, cardiovascular drugs,chemotherapeutic agents, vitamins, antiviral agents, anti-microbialagents, analgesics, anti-inflammatory agents, steroidal agents,hydrocortisone, triamcinolone, non-steroidal agents, ibuprofen,naproxen, flufenamic acid, mefenamic acid, meclofenamic acid, prioxicamand felbinac, transdermal decongestants and antihistamines.
 4. Thetherapeutic delivery system of claim 1 wherein said multiphase capsulesprovide at least one phase capable of reincapsulation.
 5. Thetherapeutic delivery system of claim 1 wherein said multiphase capsuleshave a diameter of about 0.001 micron to about 50 microns.
 6. Thetherapeutic delivery system of claim 1 wherein said multiphase capsulescomprise a cyclodextrine, waxy material, fatty material, polymer, or acombination thereof.
 7. The therapeutic delivery system of claim 1wherein said multiphase capsules comprise a double encapsulation.
 8. Thetherapeutic delivery system of claim 1 wherein said multiphase capsulesrelease said first therapeutic agent, said second therapeutic agent, orboth, upon a change in pH.
 9. The therapeutic delivery system of claim 2wherein said second therapeutic agent comprises a fragrance oil.
 10. Atherapeutic delivery system comprising: (a) a delivery medium; (b) afirst fragrance having a fruity character; and (c) an analgesic; saidfirst fragrance and said analgesic disposed within at least two deliverymechanisms.
 11. The therapeutic delivery system of claim 10 furthercomprising an anti-inflammatory agent.
 12. The therapeutic deliverysystem of claim 10 wherein said fragrance having a fruity character,said analgesic, or both are encapsulated.
 13. The therapeutic deliverysystem of claim 1Q wherein said delivery medium comprises one or moreof: a dilator, fixative, gel, starch, microcapsule, fragrance carrier,pH sensitive compound, waxy substance, polymer, cyclodextrine,cellulose, adhesive, slow release film, adhesive strip, hydrophiliccarrier particle, inorganic carrier, fatty acid, fatty alcohol, fattyester, body-activated substance, or variations thereof.
 14. Thetherapeutic delivery system of claim 10 wherein said two deliverymechanisms deliver said analgesic and said first fragrance by twoseparate modes of delivery.
 15. A therapeutic delivery system comprisingmultiphase capsules containing first and second therapeutic agents, saidmultiphase capsules containing at least one double encapsulation, saiddouble encapsulation comprising a cyclodextrine, waxy material, fattymaterial, polymer, or a combination thereof.